The power of rodent models for the elucidation of basic immunological mechanisms is unquestioned. Unfortunately, particular aspects these mechanisms may be species specific. In addition, many human infectious pathogens are incapable of establishing productive infections in rodent hosts. These factors complicate the translation of knowledge gained from such experimental animals to better approaches for the prevention, diagnosis and treatment of human diseases. The development of new strains of immunodeficient mice that can be durably xenografted with human hematopoietic cells provides a potential solution to the problems mentioned above. We have utilized the NOD/SCID/common cytokine receptor g chain knockout (NSG) strain of mice and human umbilical cord blood (UCB) CD34+ hematopoietic stem cells (HSCs) to create hematopoietically humanized mice (HISmice). We have found that these mice are reproducibly and stably engrafted with human B lymphocytes in the blood, spleen and to some extent in the lymph nodes. However, major subpopulations of the B cell compartment in these mice appear phenotypically immature. Infection of these HISmice with the spirochete bacteria Borrelia hermsii results in a course of infection and resolution via an IgM response that is qualitatively similar, but is not as robust as those observed in infected humans and mouse models. While the protective immune response to B. hermsii in mice is a T cell independent (TI) response, this response is augmented by bacterial stimulation of Toll-like receptors (TLRs). HISmice also failed to make an antibody response to purified polysaccharide antigens unless TLR ligands were given as an adjuvant. Finally, HISmice mount antibody responses to T cell dependent antigens, but these responses are weak and IgM is the predominant isotype produced. These observations lead us to hypothesize that HISmice generated as describe above, fail or respond sub optimally to a variety of pathogens and antigens due to incomplete development of their lymphocyte compartments. We hypothesize that this is due, in part, to lack of efficient cross stimulation of human cytokine receptors on engrafting hematopoietic cells by host-produced murine cytokines. In this application, we propose to test this hypothesis by generating human IL-7 and human BLyS (BAFF) expressing NSG mice for use as recipients for UCB HSCs. We predict that both of these modifications will yield HISmice with more mature and diverse B cell compartments capable of mounting robust immune responses to a variety of antigens and pathogens. As such, we predict that the resulting HISmice will serve as far better models for the development of strategies for the diagnosis and treatment of human disease.